A method for coating pharmaceutical substrates

ABSTRACT

The present invention relates to the field of coating pharmaceutical substrates. In particular, the invention relates to methods of coating of pharmaceutical substances, pharmaceutical ingredients or a blend of them. The invention also provides a method of making a pharmaceutical formulation which may be processed into a pharmaceutical dosage form, which utilizes solid pharmaceutical particles and a pharmaceutical formulation obtained by the method. The methods of the invention utilize atomic layer deposition technology. The novel methods allow difficult, moisture sensitive and electrically charged pharmaceutical substrates to be easily processable.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation application of U.S. Ser. No.14/428,530, filed Mar. 17, 2016, which is the National Phase ofPCT/FI2013/050896 filed Sep. 17, 2013, the entire contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the field of coating pharmaceuticalsubstrates. In particular, the invention relates to a method of coatingof pharmaceutical substrates and a method of making a pharmaceuticalformulation.

BACKGROUND OF THE INVENTION

Many tablets today are coated after being pressed. Coating is used tosurround or coat a pharmaceutically active ingredient or drug by atleast one layer of a surface. Coating is used for recognition, forpurposes of masking the taste, or for controlled release purposes tochange dissolution properties of active agent. Coating can also beenused to work as a barrier against atmospheric stress e.g. humidity,UV-light and oxygen to increase physical and chemical stability of theactive agent.

Various methods of coating pharmaceuticals or medical devices are known.Modern tablet coatings are polymer and polysaccharide based, withplasticizers and pigments included. The tablet coating process iscomplex, and involves parameters such as the spray pattern, drop size,and nozzle spacing, in addition to multiple other non-spray relatedparameters which must all be precisely controlled in order to ensureuniform distribution of the coating material.

Prior art discloses several methods for coating or encapsulatingpharmaceuticals. WO9002546 discloses microencapsulated pharmaceuticals,which are formed by vapor depositing a polymeric film around a corecomprising an active pharmaceutical agent to provide effectivecontrolled release activity. DE 10307568 discloses membranes useful inpharmaceutical industry, which have reduced diameter micro- or nanoporesproduced by coating film with etched or laser produced openings. US2010/0297251 discloses a method of encapsulating an activepharmaceutical agent with a controlled release coating layer using a gasphase chemical vapor deposition process. The coating materials used aremonomers or carbonaceous compounds that upon polymerization yieldpolymers or polymer films that are degradable or nondegradable.US2009/0186968 discloses atomic plasma deposited coatings over a drugattached to a porous metal substrate. The method is applicable on drugsattached or adhering to a stent surface.

Pharmaceutical industry has a great desire to reduce costs and find newapproaches for drug manufacturing and drug delivery. Current approachesof preparing pharmaceutical formulations and pharmaceutical dosage formsare complex, involve a number of technical steps, require specialadditives or treatments and result in pharmaceutical products with poorstability. In addition, most methods result in low product yields, due,in part, to the limited tolerance of the starting materials toindustrial operating conditions and the numerous technical difficultiesassociated with the coating process. Especially challenging is thedissolution and controlled delivery of poorly soluble pharmaceuticals.Undoubtedly, there is a need for more efficient methods which improveprocessing techniques and processability of drugs which have poor flowproperties and lack of compressibility. Moreover, there remains a needof developing a robust process of preparing pharmaceutical formulationswhich can be directly processed into the final dosage forms.

BRIEF DESCRIPTION OF THE INVENTION

An object of the present invention is thus to provide a method so as tosolve the above problems. In particular, the object of the presentinvention is to provide an advantageous method for coatingpharmaceuticals, which improves processability of drugs having poor flowproperties and lack of compressibility. In addition, the object of thepresent invention is to provide an effective method for making apharmaceutical formulation.

The objects of the application are achieved by a method wherein a layerof protective material is applied on the surface of a pharmaceuticalsubstrate using an ALD (Atomic Layer Deposition) method or othercorresponding technology. The objects of the application are furtherachieved by a method of making a pharmaceutical formulation, wherein thepharmaceutical substrate is first coated by ALD, an optional mixture ofthe coated substrate and excipients is formed and thereafter processedinto a desired dosage form in which solid pharmaceutical particles areutilized. The present invention also relates to a pharmaceuticalformulation obtained by the method. Additionally, the objects of theapplication are achieved by a pharmaceutical formulation consisting ofindividual pharmaceutical particles wherein each individual particlecomprises an active pharmaceutical agent and wherein each individualparticle is coated by ALD method. The present invention also relates tothe use of the ALD method or other corresponding technology for coatinga pharmaceutical substrate.

The preferred embodiments of this invention are disclosed in thedependent claims.

The inventors of the present application surprisingly noticed that whencoating of pharmaceutical substrates is performed before the processinginto a solid dosage form a significant improvement in the manufacturingprocess of pharmaceutical formulations can be obtained. The ALD coatinglayer coats the individual pharmaceutical particles allowing obtainingdosage forms composed of coated individual particles, without anyobligatory need to use excipients such as fillers, binders,disintegrants or lubricants. The properties of such a coated materialare considerably better in the further processing of the pharmaceuticalformulation into a suitable dosage form.

An advantage to the method of the invention is that difficult, moisturesensitive, electrically charged pharmaceutical substrates can be mademore easily processable. The coating generated by the method is thin,dense and smooth; moreover the coating layers deposited by ALD arepinhole-free and very conformal. The pharmaceutical formulationsobtained by the methods of the present invention are uniform in thecontent, which ensures that the same active pharmaceutical ingredientdose is delivered within each dosage form. In addition, thepharmaceutical formulations of the present invention have goodprotection against moisture, oxygen and light. Furthermore, poor drugsolubility may be overcome with an individually tailored coating toallow for modified or sustained release in a specific environment. Theconsumption of the coating material is low, and thus coating costs maybe reduced. In addition, the coated components reduce dosing andadministration of associated agents or particles.

The thickness of the coating layer may be controlled by varying thenumber of molecule layers in the coating. The term thin layer means inthis context a layer that may have any thickness between 1 nm and 500μm, the thickness depends on the pharmaceutical agent, pharmaceuticalingredients and the desired final dosage form.

The coating process of the invention is not sensitive to minor changesin the process parameters, and thus the repeatability of the method isgood. Such a uniform layer is not possible to be provided on a threedimensional object for example with CVD method (Chemical VaporDeposition) or PVD (Physical Vapor Deposition) method, since the coatingprocess may not be controlled in such a detail as with the ALD method.CVD and other similar methods also require that the coated object haveto be rotated for providing coating material over the whole surface ofthe three dimensional object.

One of the advantages of present invention is the ability toindividually coat particles on both the micro and nano scales. Theprocessing of nanoparticles has been extremely laborious due toelectricity, physical interactions and their natural tendency foraggregation.

Another advantage of the present invention is that the process issolvent free, which allows highly soluble as well as highly insolubledrug particles to be easily coated in dry form. The invention overcomesthe difficulties of using standard wet chemistry techniques with aqueoussolutions wherein highly soluble particles dissolve before they can becoated or the pharmaceutical ingredient or drug substance changes thepolymorphic form during processing. Likewise the use of organic andsometimes toxic solvents and plasticizers to apply a coating is notrequired and hence the chance of incorporation of these undesirablecompounds is eliminated.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method, wherein pharmaceuticalsubstrates are coated by Atomic Layer Deposition (ALD) or othercorresponding technology before processing into a final dosage form inwhich solid pharmaceutical particles are utilized.

A pharmaceutical substrate to be coated in the present invention may beany active pharmaceutical substance, pharmaceutical ingredient, or ablend of them which is in a solid form and capable of being depositedwithout changing structure and losing efficacy. The pharmaceuticalsubstrate may contain one or more active pharmaceutical substances orpharmaceutical ingredients. The substrate may be, for example, aparticle, granule, pellet, tablet or powder. Preferably it is aparticle. A pharmaceutical formulation is a medicinal composition,including the active pharmaceutical substance, administered in aspecific dosage form.

The term “pharmaceutical”, “pharmaceutical substance”, “therapeuticagent” or “drug” as used herein, refers to a medicinally administeredcomposition or compositions as a whole. The terms refers to the activemedicament which has a therapeutic effect intended to cure, alleviate,treat or prevent a disease or a symptom or condition suffered by thepatient.

The pharmaceutical substrate to be coated may also be a biomolecule, asmall molecule, or cells. The biomolecules may be, for example,peptides, polypeptides, oligonucleotides; nucleic acids and genes. Thesmall molecules may be, for example, nucleotides, amino acids, sugars,carbohydrates, lipids and compounds which have a molecular weight ofless than 100 kD.

Atomic layer deposition (ALD) is a generally known coating method inwhich surfaces of a substrate are subjected to alternating surfacereactions of at least a first and second gaseous precursor. OneALD-cycle is completed when the surfaces of the substrate are subjectedonce to both or all gaseous precursors. Each time the surface of thesubstrate is subjected to a precursor, a monolayer of material is formedon the surfaces of the substrate. These ALD-surface reactions arenormally substantially saturated surface reactions, meaning that theonly one monolayer of material is formed on the surfaces of thesubstrate when the substrate is subjected to a precursor. One basiccharacteristic of ALD method is the conformality of the surfacesreactions. This means that the ALD growth layers of material grow on allthe surfaces which are subjected to the precursors. Thus the coating isformed on all surfaces. In the present context the term atomic layerdeposition covers also atomic layer epitaxy (ALE) and othercorresponding coating methods in which the material growth is based onsuccessive substantially self-limiting surface reactions of at least twogaseous precursors.

One corresponding coating method is molecular layer deposition (MLD).MLD is also based on sequential, self-limiting surface reactions.However, a “molecular” fragment, which is organic and can containinorganic constituents, is deposited during MLD. The deposition ofpurely organic polymer MLD films can be achieved using step-wisecondensation reactions. Hybrid organic-inorganic films can be depositedby simply mixing organic and inorganic reactants.

Only one atomic layer is produced on the surface of the substrate duringone ALD cycle. This self-controlled growth mode contributes severaladvantages. The thickness of the films can be controlled in astraightforward manner by controlling the number of reaction cycles,therefore enabling the controlled growth of sub-nanometer thin layers.The precursors form stoichiometric films with large area uniformity andconformity even on complex surfaces with deformities and on particles.Layer-by-layer growth allows one to change the material abruptly aftereach step. This gives the possibility of depositing multicomponentfilms, so called nanolaminates or mixed oxides. It is also possible todevelop the dissolution characteristics.

In the present application pharmaceutical particle formulations areloaded into the ALD reactor and pumped down to the operating pressure ofaround 2 mbar. The ALD precursors are introduced into the reactor fromthe inlet port after which they are forced to travel through all thecells before exhausted from the exhaust port connected to the uppermostcell. During this process the desired precursor chemicals will bediffused into the matter on the cell and consequently react with itsactive surface groups forming a chemical bonding between the substratesurface and precursor molecule. In the present invention the substrateto be coated is the individual particle within the pharmaceuticalformulation. While the coating will be formed on the surface withmolecular layer accuracy the bulk properties of particle will not bechanged.

In one embodiment of the present application, paracetamol is coated withone or more molecule layers of aluminum oxide Al₂O₃. Trimethyl aluminum(CH₃)₃Al is used as a precursor and water H₂O as an oxygen source. Inthe present invention also other compounds, such as hydrogen peroxideH₂O₂ or ozone O₃ may be used as the oxygen source instead of water.

In other embodiment of the present invention, a pharmaceutical substrateis coated with titanium dioxide (TiO₂). An advantage of selectingtitanium as a coating layer is titanium's well known compatibility invivo and its track record of use in medical implants. Titanium isnontoxic and not associated with immune response.

The coating deposited by ALD may be used to mask the taste of bitterdrugs. In one embodiment of the present invention, a pharmaceuticalsubstrate is coated with a taste-improving agent, typically a sweetener,such as xylitol or sorbitol or their mixture. The coating problemspreviously associated with sweeteners, such a long coating times andmoisture sensitive sweetener material can be overcome with the presentmethod. Typical sweetener or other small molecule can be mixed withother chemicals according to the ALD coating procedure.

Precursor chemistry, process parameters and used substrates define thecoating material characteristics. The coating layer may alternativelycomprise one or more of various types of inorganic, organic and hybridorganic-inorganic polymer materials. The inorganic materials includenitrides, carbides, oxides, metals, sulfides, fluorides, etc. Inorganicoxides include, for example, silicon oxide or zinc oxide, or materialsuch as CaO, CuO, Er₂O₃, La₂O, ZrO₂, HfO₂, Ta₂O₅, Nb₂O₅, MgO, SC₂O₃,Ga₂O₃, ZnO, Y₂O₃ and Yb₂O₃ without limiting to these.

Also biomaterials, such as hydroxyapatite, polymers, sugar,nanolaminates etc. are possible materials to be deposited. ALD enables avast array of material combinations. Molecular layer deposition makespossible the deposition of organic polymers and hybrid organic-inorganicpolymers. For a review of ALD process and its exploitation we refer toPuurunen R. L. J., Appl. Phys 97 (2005), pp. 1-52. An overview of thesurface chemistry for the MLD of organic and hybrid organic-inorganicpolymers can be seen e.g. in George, S. M. et al, (2009), ACC.Chem.Res.,42, pp. 498-508.

A coating layer in accordance with the present invention may havevarious thicknesses, depending upon the particular application. In thecoating process usually a coating that is as thin as possible isdesirable such that it will be sufficiently thick in order to have thedesired properties. ALD layer thickness can also be used to control therelease of pharmaceutical substance and consequently control the drugdissolution time. The layer thickness can be defined by ALD cycles. Forexample, one ALD cycle of TMA and water results 0.1 nm thick Al₂O₃coating. In one embodiment of the present invention, wherein trimethylaluminum (CH₃)₃Al is used as a precursor, the thickness of the coatingis within the range of 1 nm to 500 nm, more preferably in the range of 1of 100 nm, most preferably from 5 to 15 nm. However, the coating layermay have any thickness between 1 nm and 500 μm. The thickness of thecoating layer depends on the pharmaceutical substance, pharmaceuticalingredients and the desired final dosage form.

The temperature used in the coating process depends on the substrateproperties and on the chosen precursor chemistry. In most common ALDmethods it is advantageous to use relatively high temperature, becauseit allows molecules to evaporate readily and a coating having asufficiently good quality is obtained. In the present invention acoating layer is deposited over a pharmaceutical substrate and thereforeheat degradation of the pharmaceutical substrate is to be avoided orreduced. For example, the melting point of ibuprofein is around 74-77°C., whereas the melting point of paracetamol is around 169-172° C. Thecoating temperature may be from room temperature (RT) up to 350° C.Preferably the temperature for pharmaceuticals is below 200° C. Ingeneral, the present invention utilizes relatively low temperatureranges in contrast to vapor deposition methods, which are conducted atmuch higher temperatures.

The present invention may utilize any suitable ALD reactor. In oneembodiment of the present invention, a static particle bed reactor isused. In this type of a reactor the particles are stationary on thereactor surface and overall and uniform coverage of each particles isdepending e.g. on effective aspect ratio that particles are forming. Oneof the main obstacles in coating pharmaceuticals or nanoparticles istheir natural tendency for aggregation. Among several factors,aggregation of cohesive particles is dependent on flow conditions aswell as the external energy that is transferred to the particles duringprocessing. Therefore, pharmaceuticals in different reactorconfigurations will show diverse aggregation patterns. Processing an ALDcoating of pharmaceutical substrates in a fluidized bed reactor ispreferred. Fluidized bed reactors offer advantages like higher heat andmass-transfer co-efficients and easy scalability. In addition due to thesuperior level of solids mixing in a fluidized bed conformally coatedindividual pharmaceutical particles are obtained. Also roll-to-roll ALDreactors may be utilized in the context of the present invention fordepositing thin films on flexible pharmaceutical substrates, such as forexample on transdermal patches.

The ALD coating according to the present invention may be used toinfluence on the particle release to the environment. For example, apoorly soluble coating allows for sustained release. Such poorly solublecoatings are e.g. aluminum oxide and titanium oxide. The coating on thepharmaceutical substance may comprise a plurality of inorganic coatinglayers or organic layers, or a combination of inorganic and organiclayers to modify drug release rate. The use of multiple coating layersmay allow for an additional degree of control in elution of apharmaceutical substance. A greater number of deposited layersincreasingly hinders elution of the drug and allows customization oftime release.

Different coating layers may be used to produce different pharmaceuticaldosage forms, such as immediate release, controlled release, and/orcombinations of both immediate and controlled release dosage forms.Controlled release dosage forms, may include particles or beadscontaining a drug or active agent, where the particles or beads arecoated with a release-controlling polymer. Controlled release beads maycomprise an inert core, coated with an inner drug-containing layer andan outer membrane layer controlling drug release from the inner layer.The inert core may be a sphere or bead of sugar, a hydrophiliccellulosic polymer, or a crosslinked hydrophilic synthetic polymer.

The ALD coating according to the present invention may also be aresponsive coating. Such a coating has a component such as ananoparticle, responsive polymer or molecule incorporated in thecoating. A responsive coating is able to give an appropriate andpredictable response to outside condition changes and thus can enhancethe performance of the pharmaceutical substance.

A pharmaceutical dosage form is a form in which a pharmaceuticalformulation is presented in the medicinal product package as supplied bythe marketing authorization holder, manufacturer, or distributor. Thekey defining characteristics of the pharmaceutical dosage form are thestate of matter, delivery method, release characteristics, and theadministration site or route for which the product is formulated.Pharmaceutical dosage forms are a mixture of active drug components andnondrug components. Depending on the method of administration they comein several types. These are liquid dosage form, solid dosage form andsemisolid dosage forms. Solid dosage forms, such as tablets andcapsules, are the most established and preferred administration route.In the present invention a dosage form may be any dosage form whichutilizes solid pharmaceutical particles. Such a dosage form may be, inaddition to tablets and capsules, suppository, vaginary, liquidpreparations, transdermal patches (transdermal drug delivery), medicalointments and emulsions (topical drug delivery, wound dressings),injection (parental drug delivery) and pulmonary drug delivery, withoutlimiting to them. These can be administrated via nasal, rectal, vaginal,ear, eye, parenteral, per oral drug delivery route, without limiting tothem.

A tablet is usually a compressed preparation that contains activesubstance, fillers, disintegrants, lubricants, glidants, binders andcompounds which ensure disintegration, disaggregation, dissolution ofthe tablet in the stomach and intestine.

In common tableting processes, the material which is to be tableted isdeposited into a cavity and one or more punch members are then advancedinto the cavity and brought into intimate contact with the material tobe pressed, whereupon a compression force is applied.

Three basic compression methods are common in most tableting operations,i.e., the wet granulation method, the double-compression method (alsoknown as dry granulation) and the direct compression method. In each ofthese methods, there are blending steps which can promote agglomerationof fine particles of the drug into larger.

In the wet granulation method, pre-weighed drug and one or more otheringredients, like a diluent, are blended. The blend is then mixed with aliquid such as water or ethanol which causes the particles toagglomerate into a damp mass. Sometimes the liquid contains a binder.The damp mass is screened to produce granules which are then dried. Thedry granules are screened to produce granules of a predetermined size.Then, the granules are typically blended with a solid lubricant andpossibly other ingredients. Lastly, the lubricated granules and anyother extra-granular ingredients are compressed into a tablet, which maysubsequently be coated.

The double-compression or dry granulation method has fewer steps thanwet granulation and does not require contact with a liquid or drying,which makes it well suited for formulating water sensitive and heatsensitive drugs. In the double-compression method, the drug and otheringredients, such as a lubricant, are blended and then compressed in afirst compression step. There are two conventional first compressiontechniques. One is roller compaction where the blend is fed betweenrollers which press it into sheets and the other is slugging where theblend is compressed into slugs, which are tablet-like forms that aretypically larger than tablets intended for human consumption. Theresulting sheets or slugs are then comminuted into granules, mixed witha solid lubricant and compressed in a second compression step to producethe final tablet.

The direct compression method is the simplest of the three well knownmethods for making compressed solid dosage forms. In the directcompression method, the drug and any other ingredients are blendedtogether and directly compressed into the final tablet. For variousreasons, however, not all components which can be employed for theformulation of tablets are suitable for use in this process due to poorcompressibility, flowability and stability under conventional tabletingconditions.

The present invention relates to a procedure for preparing apharmaceutical formulation and to a pharmaceutical formulation obtainedby the process. In accordance with the present invention thepharmaceutical substrates are first coated by ALD after which all of thecomponents, i.e., the coated active pharmaceutical substance, optionallyany additional excipient(s) and other ingredient(s), are mixed togetherand processed into the final pharmaceutical dosage form. The finaldosage form may be any dosage form which utilizes solid pharmaceuticalparticles. The present invention allows compression of thepharmaceutical substances directly after coating. In accordance with thepresent invention it is also possible to first coat the pharmaceuticalsubstance and the excipient together and then proceed in manufacturingthe dosage form. Alternatively, the excipient may be coated alone beforemaking the pharmaceutical formulation.

The ingredients in the pharmaceutical formulation are mixed togetherusing techniques well known in the art until the mixture is homogenouswith respect to the drug. It is important that all ingredients arefairly dry, powdered or granular, somewhat uniform in particle size, andfreely flowing. The pharmaceutical particles may be reduced in aparticle size using conventional milling techniques, such as air jetmilling, ball milling, cad milling, multi milling and other suitablesize reduction techniques.

In a preferred embodiment the processing into the final dosage form isdone by compressing. The term “compressing” includes any known processperformed by applying compression forces. These methods include, but arenot limited to, compression, compaction, extrusion and injectionmolding.

In one embodiment of the present invention the pharmaceutical dosageform is a tablet. Some active pharmaceutical agents may be tableted aspure substances, but this is rarely the case; most formulations includeexcipients, which are pharmacologically inactive ingredients added tohelp holding the tablet together and giving it strength. Thepharmaceutically acceptable excipients may be selected from the group ofdiluents, surfactants, antioxidants, disintegrants, binders, lubricants,glidants, and chelating agents. Pharmaceutically accepted excipients arewell known in the art and in this context we refer to e.g. Handbook ofPharmaceutical Excipients, 6th edition, Pharmaceutical Press andAmerican Pharmacist's Association by Ray C. Rowe, Paul J. Sheskey andMarian Quinn. It should be noted that a tablet obtained by the method ofthe present invention may be further coated after being pressed to getfor example a sugar-coated tablet or a film-coated tablet.

After making the final tableting blend for the pharmaceuticalformulation, a lubrication step is used to ensure that the tabletingblend does not stick to the equipment during the tableting process. Thisusually involves low shear blending of the pharmaceutical ingredientswith a powdered lubricant, such as magnesium stearate or stearic acid.

Any conventional tablet presses, also called tableting machines, may beused from a hand-operated press or a single station tableting press to amulti-station rotary press. The operation of such machinery is wellwithin the ordinary skill in the art.

The present invention relates also to a pharmaceutical formulation,wherein the pharmaceutical substrate is distributed as particles, andwherein the coating layer is deposited by ALD and the coating layerconformally coats over the individual particles of the pharmaceuticalsubstrate. In one embodiment of the invention, the pharmaceuticalformulation is in a dosage form which utilizes solid pharmaceuticalparticles, preferably it is a tablet.

The present invention also relates to the use of the ALD method or othercorresponding technology for coating a pharmaceutical substrate.

It will be obvious to a person skilled in the art that as the technologyadvances, the inventive concept can be implemented in various ways. Theinvention and its embodiments are not limited to the examples describedbelow but may vary within the scope of the claims.

Examples Example 1 Pharmaceutical Substrate Coating

Pharmaceutical particles (as shown in Table 1) were coated by Beneq TFS500 ALD tool, equipped with static particle bed reactor. This type ofparticle reactor is suitable for small amount of particles. The reactoris built up from five cells top of each other. Each cell is 200 mm ofits diameter and 20 mm of its height. Paracetamol powder was loaded onthe bottom of the reactor cells without any pretreatment and the reactorcells were then loaded into the reactor and pumped down to the operatingpressure of around 2 mbar. Al₂O₃ and TiO₂ were deposited on paracetamolparticles with average particle size of approximately 50 μm attemperature of 100 to 140° C. Al₂O₃ films were grown fromtrimethylaluminum (TMA) and water vaporized from the source at atemperature of 20° C. TiO₂ films were grown fromtetrakis(dimethylamido)titanium (TDMAT) vaporized from the source at atemperature of 41° C. and water vaporized from the source at atemperature of 20° C. One deposition cycle for Al₂O₃ consisted of a 2seconds metal precursor (TMA) pulse, 2.5 seconds N₂ purge, 0.5 secondwater pulse and 1 second N₂ purge. Similarly the timing sequence usedfor TiO₂ deposition was 1-5-1.5-2 seconds. The number of ALD cyclesdeposited for both oxides was 500.

Paracetamol (USP) was purchased from Hawkins Inc. (Hawkins Inc., MN,USA), mannitol was purchased from Roquette Freres, Lestrem, France,D-sorbitol from Sigma Aldrich and xylitol was commercial foodstuff.

Example 2 Tableting Study

The material obtained from Example 1 was tableted using an instrumentedeccentric tableting machine (Korsch EK-0, Erweka Apparatebau,Heusenstamm, Germany) Flat-faced 9 mm punches were used and the die wallwas lubricated using 5% (w/V) magnesium stearate in acetone before eachcompression. The target weights of tablets were 300 mg. Compressionforces during the compression process were measured and the crushingstrength of each tablet was measured using Scleuninger-E apparatus(Switzerland) (Table 1).

TABLE 1 Compression forces and the crushing strength of the resultingtablets Upper punch Crushing strength Material force (kN) (N) Neatparacetamol *   8 kN No tablet, no measurable crushing strengthParacetamol + Al₂O₃ 3.6 kN 62N coating Paracetamol + TiO₂ 8.7 kN 10Ncoating Paracetamol + Xylitol 7.4 kN  5N 50%/Sorbitol coating 50% (w/w)^(a)) * no coating ^(a)) amorphous blend deposited using ALD equipment

The results presented in Table 1 show that flowability andprocessability of the ALD coated pharmaceuticals is better than in pureparacetamol.

1.-6. (canceled)
 7. A method of making a pharmaceutical formulation, themethod comprising: coating particles of a pharmaceutical substrate byatomic layer deposition to produce individual coated particles of thepharmaceutical substrate; and processing said coated particles into adosage form, which utilizes solid pharmaceutical particles.
 8. Themethod of claim 7, wherein said processing employs compression of thecoated particles into the dosage form.
 9. The method of claim 8, whereinsaid dosage form is a tablet. 10.-13. (canceled)
 14. The method of claim7, wherein the coating layer comprises an inorganic or organic materialor a combination thereof.
 15. The method of claim 14, wherein theinorganic material comprises a metal oxide.
 16. The method of claim 15,wherein said metal oxide is aluminum oxide or titanium oxide.
 17. Themethod of claim 14, wherein said inorganic or organic material comprisesa tastemaking agent.
 18. The method of claim 17, wherein thetaste-masking agent is a sweetener.
 19. The method of claim 17, whereinthe taste-masking agent is a sugar alcohol.